Compliant venous graft

ABSTRACT

A venous graft for replacement of a section of an artery and methods of making the graft. The graft comprises a flexible, resilient, generally tubular external support and a vein segment carried within and having an ablumenal surface in contact with and supported by the tubular support, the venous graft being capable of resilient radial expansion in a manner mimicking the radial compliance properties of an artery.

CROSS REFERENCE

This application claims priority to U.S. Provisional Application Ser.No. 60/466,226 titled “Compliant Venous Stent” filed on Apr. 28, 2003,incorporated herein by reference.

FIELD OF THE INVENTION

This invention involves a venous graft involving a vein segment and asupportive sheath chosen to provide the graft with mechanical complianceproperties which resemble those of a healthy native artery.

BACKGROUND OF THE INVENTION

Various types of vascular prostheses are known or available.Commercially available synthetic vascular grafts in use are commonlymade from expanded polytetrafluoroethylene (e-PTFE), or woven, knitted,or velour design polyethylene terephthalate (PET) or Dacron®. Theseprosthetic vascular grafts may have various drawbacks. When used forrepairing or replacing smaller diameter arteries, these grafts may faildue to occlusion by thrombosis or kinking, or due to an anastomotic orneointimal hyperplasia (exuberant cell growth at the interface betweenartery and graft). Another problem may involve expansion and contractionmismatches between the host artery and the synthetic vascularprosthesis, which may result in anastomotic rupture, stimulatedexuberant cell responses, and disturbed flow patterns and increasedstresses leading to graft failure.

Problems also exist with the use of autologous saphenous vein grafts inthese applications. Use of autologous saphenous vein grafts to bypassblockages in coronary arteries has become a well-established procedure.However, their success in the long term has been limited. In thecoronary position, the literature reports a low (45-63%) patency of veingrafts after 10-12 years. It is believed that these failures result fromremodeling of the implanted vein in response to greatly increasedinternal pressure, that is, as the vein is required to function as anartery. In general, arteries have substantial musculature and, althoughable to expand diametrically in response to increased internal pressure,are capable of withstanding normal arterial pressure variances. Veins,on the other hand, are not required to withstand arterial pressurevariances and are relatively incapable of withstanding the higherarterial pressures without substantial bulging. In this regard, thenominal venous diameter seen under nominal venous pressure is seen toapproximately double upon exposure to arterial pressure.

Increases in lumenal diameter of these magnitudes in vein segmentimplants are accompanied by increases in tangential stress. Tangentialstress has been shown to be proportional to the lumenal radius-wallthickness ratio. In healthy arteries, this ratio remains constant acrossmultiple species. However, this does not occur in veins. It is believedthat a vein's smooth muscle cells increase their growth rate and secreteextra-cellular matrix components in response to such increases intangential stress. This becomes a remodeling response, and is likely anattempt by the vein to reduce the lumenal radius-wall thickness ratio,and consequently the tangential stress. However, it appears that thesereactions overcompensate in the veins, resulting in the phenomenon ofneointimal hyperplasia yielding grossly thickened and stiff graft walls.As the dilation of the vein segment continues, the resulting mismatchbetween the vein and artery diameters may lead to disturbance of flowpatterns, which may also favor the formation of thrombi.

A venous graft that reduces or eliminates such failings in the prior artis required.

SUMMARY OF THE INVENTION

It has now been found that a vein segment, if externally supported by anappropriate, flexible, radially-resiliently tubular support, canfunction, in much the same fashion as the artery to be replaced. Thatis, it functions without undue bulging or aggravated mismatchingphenomena leading to graft failure. Unless otherwise indicated, the term“compliance” means the ratio of the diameter change of a vessel as itexpands in the radial direction in response to a given change in vesselpressure, and the values for compliance referred to below result fromdynamic, in vitro testing. As described in greater detail below, thecompliance of venous graft is largely dependent upon the compliance ofthe external, radially resilient support.

The invention in one embodiment, accordingly, relates to a flexible,resilient, generally tubular external support within which may besupported a vein segment to form a venous graft. The tubular support iscapable of resilient radial expansion in a manner mimicking thecompliance properties of an artery, and compliance figures in the rangeof 3 to 30%/100 mm Hg are appropriate. The tubular support may be formedof a knitted or woven fiber mesh that is so formed as to exhibit theneeded compliance properties.

The invention in certain embodiments provides a venous graft forreplacement of a section of an artery. The graft comprises a flexible,resilient, generally tubular external support and a vein segment carriedwithin and having an ablumenal surface in contact with and supported bythe tubular support, the venous graft being capable of resilient radialexpansion in a manner mimicking the compliance properties of an artery.Compliance figures in the range of 3 to 30%/100 mm Hg are appropriate.The tubular support may take the form of a fiber mesh, such as aknitted, braided or woven mesh, the fibers of which may, if desired, beappropriately crimped to provide the required resiliency and compliance.

In other embodiments, the invention relates to a method for producing avenous graft for use in replacing a section of an artery. A segment of avein is provided, and is sheathed in a generally tubular support insupportive contact with the ablumenal surface of the vein segment. Thesupport is sufficiently flexible and radially resilient as to providethe resulting graft with compliance properties mimicking the complianceproperties of an artery. Sheathing of the vein segment within thetubular support may be accomplished by supporting the generally tubularsupport upon an exterior surface of an applicator having an internalpassage within which is positioned the vein segment, and removing theapplicator to permit the tubular support to come into supportive contactwith the ablumenal surface of the vein segment. Axial dimensionalchanges in the tubular support may be controlled as necessary to providethe venous graft with the desired compliance properties mimickingarterial compliance properties.

Other embodiments of the invention relate to venous grafts that includea flexible, resilient, generally tubular external support formed of ashape memory alloy, and a vein segment carried within and having anablumenal surface in contact with and supported by the tubular support.The shape memory support may be placed around a vein segment when theshape memory material is in a first enlarged configuration. The tubularsupport comes into supportive contact with the ablumenal surface of thevein when the support is transformed, as by a temperature increase, intoa second configuration different from the first configuration. The shapememory support in its second configuration may exhibit superelasticproperties and in any event is sufficiently flexible and resilient as toprovide the venous graft with compliance properties mimicking thecompliance properties of an artery. Compliance figures in the range of 3to 30%/100 mm Hg are appropriate. The tubular support may take the formof a wire mesh made of shape memory alloy, such as a knitted or wovenmesh, the wires of which may, if desired, be appropriately crimped toprovide the required resiliency and compliance.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a pressure versus diameter graph typifying the characteristicsof a native vein, native artery, a non-compliant stented vein, and acompliant stented vein;

FIG. 2 is a schematic cross-sectional view of an artery;

FIG. 3 is a representative pressure versus strain graph;

FIG. 4 is a pressure versus graft diameter graph;

FIG. 5 is a photograph of a tubular support in a first configuration,shown in an axially compressed and radially expanded configuration andsupported on a plastic tube;

FIG. 6 is a photograph of the tubular support of FIG. 5 in an axiallyelongated and radially reduced configuration to conform to a vein outerdiameter;

FIG. 7 is a side view of the graft of FIG. 6, showing a length-governingelement;

FIG. 8 is a schematic view of braided elements;

FIG. 9 is a perspective view of a braided tubular support;

FIG. 10 is a schematic view of knitted elements;

FIG. 11 is a side view of a section of a knitted tubular support;

FIG. 12 is a view of angular pre-braiding crimped elements;

FIG. 13 is a perspective, schematic view of an angular pre-braidingcrimped tubular support;

FIG. 14 is a view of rounded pre-braiding crimped elements;

FIG. 15 is a view of angular pre-knitting crimped elements;

FIG. 16 is a view of rounded pre-knitting crimped elements;

FIG. 17 is a broken-away, perspective view of a post-braiding crimpedtubular support;

FIG. 18 is a broken-away, perspective view of a venous graft showing aportion with anti-fraying element;

FIG. 19 is a broken-away, perspective view of one embodiment utilizingan applicator for assembling a venous graft;

FIG. 20 is a broken-away, perspective view of the use of a modifiedapplicator for assembling a venous graft; and

FIG. 21 is a photographic, perspective view of a section of a knittubular support.

DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED EMBODIMENTS

Applicants have recognized that significant deficiencies attend to thepast methodologies and devices relating to the increased pressuresexperienced by vein grafts utilized in arterial positions. The increasedpressures lead to excessive dilation of vein grafts in arterialcirculation, leading to the development of intimal hyperplasia, whichcauses occlusion of the vessel.

Intimal hyperplasia is believed to be a primary reason for vein graftfailure. In this context it is known that intact endothelium acts in amanner to protect against the proliferation of underlying vascularsmooth muscle cells, known as VSMC. The intact endothelium also plays arole in VSMC contractile responses. The VSMC have also been shown torelease factors with long term physiological effects on the endothelialcells, including maintenance of a non-proliferative state. Bycomparison, the pathogenesis of intimal hyperplasia in a vein graft mayfollow the sequence of dilatation under arterial pressure;overstretching to maximum capacity; disruption of borders of endothelialcells; rupture of internal elastic membranes; migration of smooth musclecells into the intimal layer and resultant unbalanced proliferation;atrophy of media and further consolidation of stiffness; and graftarteriosclerosis with traumatic media necrosis and atrophy, as well aspathological surface and wall stress and strain. These phenomena mayresult in a decrease in vein graft patency within six years. Intimalhyperplasia may be observed in such grafts from about 16 months, whileanastomotic intimal hyperplasia may occur at about 18 months, andarteriosclerosis may occur from about 45 months.

Others have attempted to overcome certain of these problems by use ofmetallic or polymeric external structures designed to arrest thedilation of the vein graft. FIG. 1 graphs blood pressure against vesseldiameter, with D₀ representing the vessel diameter at zero pressure. Asshown in this graph, lines 16, 18 represent the normal diastolic, i.e.low (80 mm Hg) and normal systolic, i.e. high (120 mm Hg) physiologicalblood pressure range for humans. Point 21 may represent the diameter ofan artery (D_(A)) at 100 mmHg, and point 23 may represent the diameterof a vein (D_(V)) at the same pressure of 100 mmHg. An unstented nativeartery reacts to pressure loading as shown at line 32, and an unstentedvein reacts to the same loading as shown at line 35. The use of knownstents with vein grafts results in movement of line 35 in the directionshown by arrow 38, resulting in the approximate profile indicated atline 42 showing the response of a pressure loaded vein and non-compliantstent combination. Although this prevents over-dilation, and someadvantage accrues, this may lead to further unhealthy sequelae. Also, tothe extent that vein-stent combination devices may be shown to limitsome of the dilation and intimal hyperplasia in the mid-graft region,they may not be able to prevent intimal hyperplasia at the anastomoses.This can be a significant problem for vein grafts that are transplantedinto the arterial circulation vasculature. Prior attempts to resolvethese problems fail to recognize the full implications of a vein beingused in these situations. Accordingly, factors in the design of avein-graft that may have a significant impact on its long term patencymay have been missed.

One important factor in proper remodeling is that of proper cyclicstretch. Applicants are able to incorporate this concept into vein-stentgrafts of the invention. In similar manner, the role of vascularendothelial growth factor (VEGF) in vascular smooth muscle cells may bevery important to the design of a preferred arterial vein-stent graft.It is known that low concentrations of VEGF may play a role inpreserving and repairing the arterial lumenal endothelial layer.Further, it is suggested that activation of the VEGF receptor KDR isaffected by cyclic stretch. Applicants believe that the phenomenon ofupregulation of VEGF expression by physiological stretching of vascularsmooth muscle cells is one reason for redesigning a vein-stent graftwhich has improved, controllable cyclic stretch features.

A further consideration is the influence of tensile stress/strain on thestructure and organization of smooth muscle cells during development andremodeling, particularly as to the orientation of such cells. In alarger topographical sense, this may also relate to the role of bloodflow in the formation of focal intimal hyperplasia in known vein grafts,including inducement of eddy blood flow at locations of graft-hostdiameter mismatch.

These considerations and deficiencies can be addressed with the variousstructures and methodologies of the present invention in which a veingraft is provided that exhibits compliance properties mimicking those ofhealthy arteries. Radial expansion and contraction of the graft ispermitted in a manner that mimics the radial expansion and contractionof an artery to at least closely approach the desired result in whichthe vein graft, its connections to adjacent arterial ends or stumps, andthe adjacent arterial portions tend to expand and contract in a similarmanner, to thereby substantially avoid anastomotic compliancemismatches. This is accomplished through the use of a flexible,resilient, generally tubular external support that engages the ablumenalsurface of a vein segment carried within the support, the support beingso fabricated as to functionally provide the graft with the complianceproperties of an artery.

Compliance Properties

As noted earlier, compliance is the ratio of the diameter change of avessel in the radial direction to a given change in vessel pressure, andthe values for compliance referred to below result from dynamic, invitro testing. Compliance values are reported here as percentage changesin the internal diameter of a vessel per a 100 mm Hg change in vesselpressure, as measured in the range of normal blood pressures, that is,from about 80 mm Hg to about 120 mm Hg. In the laboratory, it isconvenient to measure compliance through the use of an elongated balloonstructure over which a candidate tubular support is positioned.Distilled water at about 37° C. is pumped into the balloon to cause itto inflate, and the pressure within the balloon is cycled between 0 mmHg and 140 mm Hg at a frequency of about 72 cycles per minute to mimic anormal pulsatile blood flow. The change in internal volume is measuredbetween 0 mm Hg and 140 mm Hg to provide pressure/volume data. From thisdata is subtracted the pressure/volume data resulting from repeating theprocedure with the balloon alone, and from the resulting pressure/volumedata the percentage change in the internal diameter of the tubularsupport between 80 and 120 mm Hg can be calculated. It is convenient toexpress this radial compliance value as %/100 mm Hg.

The compliance of an implanted venous graft may be measured in vivothrough the use of ultrasound techniques in which the vein graft isvisualized in a cross-sectional view and the dimensional change of thevessel with varying blood pressure is recorded for at least one andusually a number of cardiac cycles. The cross-sectional lumenal area ofthe vein graft is measured for the smallest cross-sectionalconfiguration and the largest cross-sectional configuration for onecardiac cycle. The smallest cross-sectional configuration of the veingraft lumen is associated with diastolic blood pressure whereas thelargest cross-sectional configuration is associated with systolicpressure. The cross-sectional lumenal area values for diastolic andsystolic blood pressure are used to calculate the lumenal diametervalues and the vein graft compliance. Compliance values of a venousgraft measured in vivo often are slightly larger that the compliancevalues measured in the laboratory, and the compliance values referred toherein are laboratory values resulting from the in vitro measurementsdescribed above

FIG. 2 is a sectional representation of vascular tissue useful forillustrating the relation of the natural arterial structure with theprosthetic venous graft structure of the invention. The naturaladventitial layer 95 of an artery 98 is comprised of two main tissuetypes that contribute to the mechanical properties of the naturalartery, namely elastin and collagen. The mechanical properties of thesetwo soft tissue components are described in Table I below: TABLE I SoftTissue Elastic Modulus (Pa) Max Strain (%) Elastin 4 × 10⁵ 130 Collagen1 × 10⁹ 2-4

As shown in the above table, these two soft tissue types have largedifferences in mechanical properties. Elastin is very elastic, andcollagen is very stiff in comparison. These two tissue types arecombined in the adventitial layer to produce a non-linear elasticresponse. As shown in FIG. 3, the combined effect of the characteristicsof elastin 101 and collagen 104 (having a greater role at higherstrains) results in a non-linear response curve (shown loading at 135and un-loading at 137) within the physiological pressure range of anatural artery between about 80-120 mm Hg. This characteristic ofpulsatile expansion and contraction of arteries requires fine mechanicalcompliance of any prosthetic graft, i.e., a close mimicking by theprosthetic device of the mechanics and timing of the natural arterydistending and reshaping under change in blood pressure.

From an engineering standpoint, the following relationships may behelpful from a design standpoint in producing venous stent grafts of theinvention.$C_{d} = {\frac{\Delta\quad D}{D_{diastolic}\Delta\quad P} \times 100 \times 100\quad{mmHg}}$in which C_(d) is compliance, P is blood pressure, D is vessel diameter,and ΔD represents the diameter change between systolic and diastolicpressures.

The stiffness of blood vessels is stated as a stiffness index (β), andis a measure of the changes of curvature and diameter, stated as:$\beta = {\frac{\ln\frac{P_{systolic}}{P_{diastolic}}}{\frac{\Delta\quad D}{D_{diastolic}}} = {D_{diastolic}\frac{{\ln\quad P_{systolic}} - {\ln\quad P_{diastolic}}}{\Delta\quad D}}}$

A related characteristic of blood vessels is that of elastic modulus(K), which is considered a measure of stiffness, and is stated as:$K = {\frac{V_{diastolic}\Delta\quad P}{\Delta\quad V} \propto \frac{D_{diastolic}\Delta\quad P}{\Delta\quad D} \propto \frac{1}{C}}$in which C is compliance. In terms of diametric compliance, as anexample,$K = {{D_{diastolic}\frac{P_{systolic} - P_{diastolic}}{D_{systolic} - D_{diastolic}}} = {D_{diastolic}\frac{\Delta\quad P}{\Delta\quad D}}}$

FIG. 4 shows that the Elastic Modulus (K), as defined in aboveequations, is proportional to the secant S₁ of the pressure-diametercurve PD₁, plotted on a linear scale (left y-axis in FIG. 4), betweendiastolic and systolic pressure. The slope,(P_(syst)−P_(diast))/(D_(syst)−D_(diast)), of the secant S₁ is a goodapproximation to the slope of the pressure-diameter curve PD₁ in thatpressure range. From the above equations for the Elastic Modulus (K) itcan be appreciated that the Elastic Modulus (K) is not equal to theslope of the secant S₁ but is proportional to the slope by a factorD_(diastolic). Compliance (C_(d)) is approximately proportional to theElastic Modulus (K) hence it is approximately proportional to theinverse of the secant S₁ of the pressure-diameter curve PD₁ betweendiastolic and systolic blood pressure.

The stiffness index (β) is proportional to the secant S₂ of thepressure-diameter curve PD₂ between diastolic and systolic bloodpressure when the pressure-diameter curve is plotted on a logarithmicpressure scale (right y-axis in FIG. 4). The slope of the secant S₂ is(In P_(syst)−ln P_(diast))/(D_(syst)−D_(diast)) and is a goodapproximation to the slope of the pressure-diameter curve PD₂ in thatpressure range. It can be again appreciated, from the above equationsfor the Stiffness Index (β) that the Stiffness Index (β) is not equal tothe slope of the secant S₂ but is proportional to the slope by a factorD_(diastolic).

Compliance data of natural human vessels is categorized by vessel typeand by age of the vessel (i.e., age of patient). For example, a commoncarotid artery has about a 6.6%/100 mm Hg compliance value. The valuesfor a superficial femoral artery and a femoral artery are 6-10%/100 mmHg. A value for a saphenous vein, however, is about 4.4%/100 mm Hg,while an aorta ranges generally from about 20-50%/100 mm Hg, dependingon the location. Also, the lengths of grafts according to location inthe body must be considered, and substantial lengthwise variance ingraft lengths is not uncommon. It is also known that the diameter ofvarious arteries change over time, and this may have a significantimpact on overall compliance values. Returning to FIG. 1, line 80represents the pressure-diameter data that certain embodiments of venousgrafts of the invention seek to emulate, wherein the complianceproperties of a native artery (line 32) is closely mimicked.

Support Materials and Manufacture

The radially resilient support may be manufactured from any biologicallyacceptable material that possesses the ability to be shaped into atubular structure having the required compliance. Polymeric fibers maybe employed, such as polyurethanes, polyethylene terephthalate,polypropylene, and polytetraflouroethylene, and good results may beobtained through the use of wires of such metals as stainless steel andcobalt-chromium alloys. Wires made of shape memory alloys such asnitinol may be used to advantage. Shape memory elements or filaments maybe made of one or more shape memory materials as exemplified in thefollowing table, it being understood that this is not to be consideredan exhaustive list. Also, any metal or metal alloy may be coated with apolymer for improved biocompatibility, recognizing that the polymer mayor may not be biodegradable. ALLOYS POLYMERS Ag—Cd Two component systembased on oligo(Σ-caprolactone)dimethacrylate and N-butyl acrylate Au—CdPolyurethanes Cu—Al—Ni Polynorborenes Cu—Sn Poly(ether ester)sconsisting of poly(ethylene oxide) and poly(ethylene terephthalate)(EOET copolymers) Cu—Zn Ethylene vinyl acetate copolymers Cu—Zn—SiPolystyrene polybutadiene copolymer Cu—Zn—Sn Cu—Zn—Al In—Ti Ni—Al Ni—TiFe—Pt Mn—Cu Fe—Mn—Si

With respect to shape memory alloys, other design considerations includetemperatures, different diameters and radial compliance, shapetransformation dimensional changes, and wire thicknesses. Generally,shape memory alloys and shape memory polymers may have transformationtemperatures which are below physiological temperatures, i.e., 37° C.,to ensure self-righting responses. Preferably, transformationtemperatures will also be above room temperature to ensure that theshape memory material reinforcing does not need to be refrigerated forstorage purposes. Thus, the ideal shape memory transformationtemperatures will likely be between 21° and 37° C. This transition mayeither be a two-way or a one-way directional transition, with acurrently preferred embodiment including a two-way directionaltransition. The transition temperature range can either be a short, i.e.0.5° C., or a long transition temperature range, i.e. 10° C., where theshape is proportionally regained over this temperature range. Forexample, for a desired temperature transition to be 100% complete at 25°C. but with it starting at 20° C., then this would yield a temperaturerange of 5° C. The changes in radial diameter due to the shape memorymaterial experiencing transformation dimensional changes is preferablyin a range of from 5% to 30%.

An embodiment of a tubular support utilizing a shape memory alloy isillustrated in FIGS. 5 and 6. FIG. 5 shows an arterial reinforcementtubular support 77 formed of one or more shape memory material elements165. These elements are braided, but may also be knitted, into agenerally tubular structure designed for placement around a portion of avein to produce an arterial graft. In this example, a shape memory alloyis employed because of its so-called “superelastic” properties ratherthan its ability to undergo temperature-induced phase changes, althoughsome phase change from austenite to stress-induced martensite may occur.In FIG. 5, the braided tube is positioned on a hollow plastic straw asrepresenting a vein segment, and has been compressed axially to producean increase in diameter. By extending the braided tube axially, as shownin FIG. 6, the tube becomes reduced in diameter to provide support tothe vein segment.

The shape memory braided material shown in FIGS. 5 and 6, if used alsofor its phase transformation properties, may be supplied in a firstconfiguration (which may be in the martensite phase) which can be easilymanipulated to receive a vein segment 86 within the structure, and asecond configuration (shown in FIG. 6, which may be in the highertemperature austenite phase) which has a “remembered” narrower diameterconfiguration to provide support to the vein segment. The contact ofinner surfaces 170 of the structure with ablumenal surfaces 175 of thevein segment 86 is shown also in FIG. 7. The resilience of shape memorymaterials can be controlled by altering compositions, temperingprocedures, wire diameters, etc., so that a tubular support fashionedfrom this material may mimic (when combined with the minimal mechanicalvalues of a vein segment) the compliance values of a host artery inorder to optimize the venous graft-artery interaction. This aspect ofcompliance mimicking has components of expansion, recoil, timing, andtissue remodeling. In this example, the vein-stent compliance values arechosen to closely mimic those of a healthy native artery. Whereas theshape memory wires are shown as braided in these figures, they may alsobe knit, and in fact the knit configuration appears to be offer certainadvantages.

Radially resilient tubular supports may be knit from metal wire, such asstainless steel and cobalt-chromium alloys. Metal wires ranging indiameter from about 25 to 150 micrometers are appropriate for knitsupports with diameters in the range of 35 to 50 micrometers beingparticularly useful, although larger or smaller diameters may beemployed as desired. For braided tubular supports, metal wires rangingin diameter from about 37 to about 170 micrometers are appropriate,although larger or smaller diameters may be employed.

Knitting procedures may be performed by known methods using, forexample, a LX96 knitting machine manufactured by the Lamb KnittingMachine Corporation. Favorable radial compliance and tubular dimensionalproperties may result from knitting the tubular structure in a mannerproviding loops that alternate in the circumferential direction betweenlarger and smaller loops, as shown in FIG. 21. In this Figure, smallerloops 250 are shown alternating circumferentially with larger loops 251.Such alternating loop sizes typically present themselves visually aslongitudinal stripes extending axially along the tubular support, as theadjacent loops of each size align in the longitudinal axis. Each closedend of the loop may be either rounded or generally square-shaped orvariations in between, and, the sides of the loop may turn outward, beparallel, or turn inward. The latter design has shown some advantage inacting like a spring and assisting in the stability of the overalldimensions of the tubular structure, and maintaining its compliancecharacteristics.

The knitted or braided tubular support may then be subjected to crimpingto provide crimps extending, for example, about the circumference of thetubular support (that is, in the manner shown in FIG. 17). One way ofdoing this is through the use of an axially fluted mandrel that isinserted into the tube and is pressed outwardly against a wall of thetube to force the wall against a complementary shaped outer female moldto bend the knitted or braided wires and to form a circumferentialcrimp, the crimp resulting from each flute or raised ridge of themandrel extending axially of the support.

A compliant venous graft using various metals or polymers for thetubular support may be provided in several ways. Embodiments may beadvantageously provided in knitted form. FIGS. 8 and 9 show material 165in a braided configuration, and FIGS. 10 and 11 show material 165 in aknitted configuration. Mechanical characteristics of the tubular supportmay be enabled by the type of shaping and relational structures formedon the elements making up the knit or braided structures. It iscontemplated that a technique involving crimping of the material 165 toachieve angular crimps (shown in FIGS. 12 and 13), formed prior to thebraid or knit construction, and rounded crimps (shown in FIG. 14) mayprovide acceptable results. Crimping techniques that may be appropriatewith pre-knit configurations, are shown in FIG. 15 (angular crimps) andFIG. 16 (rounded crimps). Another technique for achieving certainperformance characteristics of braided or knitted shape memory materials165 is to perform crimping after braiding or knitting, i.e.post-braiding or post-knitting. FIG. 17 shows one embodiment of material165 formed in a braided configuration and having a post-braided crimpingoperation applied to form a crowned pattern to achieve desired crimpcharacteristics.

Crimp angle and pitch density may be important variables in certainembodiments of the current design of the tubular supports. It isunderstood, however, that certain advantages of this invention may stillbe achieved without use of crimping. Ranges of crimp angle arepreferably from about 10° to 85° to the line of lay of the reinforcingwire or braid. The crimp size may vary from 0.01 to 5 mm in length. Itis desired that the braid or helical wires have a pitch angle that mayvary from about 5-85° to the axial length of the vein graft.

Applicants have identified certain crimping techniques that relate tocrimping either before or after braiding or knitting. For example, inpost-braid crimping the material braids are produced according toexisting techniques, after which macroscopic longitudinal crimping isimparted to the tubular mesh using a post-braid crimping tool. However,according to the material and specific configuration of the stent, ifthe post-braid crimping of braided tubes does not achieve sufficientcompliance then alternate methods are possible. One example is to effectpre-braid crimping, thereby setting the memory of a shape memorymaterial in a crimped configuration and subsequently straightening thematerial before braiding. The crimp is thus induced upon exposure tophysiological temperatures.

The external tubular support adjusts the mechanical and geometricalproperties of the vein graft to match or mimic healthy arterialproperties and therefore adapt to the arterial pressure of the hostartery. Accordingly, this results in substantial matching of the lumenof the vein graft and the host artery, the substantial matching ofcompliance of the vein graft and the host artery, and substantialmatching of the radius to wall thickness ratio (r/wt) of the vein graftto the host artery. As noted above, optimization of the vein-stentcompliance should ensure that the vein-stent graft mimics the behaviorof arteries regarding the non-linear stiffening with increasing diameterdue to elevated blood pressure, “locking” at a maximum pressure, andthen demonstrating dynamic recoil in a timely manner.

When venous grafts utilizing knit or braided tubular supports are cut atangles suitable for end-to-end anastomoses, either at generally rightangles or in scallop-like shape, the ends of the supports may experiencefraying (see, for example, FIG. 17). Certain methods and structure arehelpful to eliminate such fraying. In one embodiment, adjustable rings210 of bioabsorbable or biodegradable material are placed generallycircumferentially around a portion of the material 165, and in contactwith external surfaces 217, as shown in FIG. 18. The number of rings maybe varied as needed. The location of the rings may be adjusted to theposition of anastomoses where vein and tubular support need to be cut.The cut or suture may be carried out through the ring, and the ring maybe absorbed or degraded over a predetermined time, as desired.

Another embodiment of a structure to prevent fraying of a knit orbraided tubular support when it is cut is the use of polymer coating forthe fiber mesh. This feature may also provide the benefit of preventinggluing of joints and contact zones of elements of the stent. However,use of the radially compliant tubular support as a reinforcing structuremay advantageously involve bonding of the ablumenal surface of a veinsegment to confronting internal surfaces of the support. This attachmentor connection may be accomplished through the use of a glue or othermaterial having adhesive or connecting characteristics. In oneembodiment, a fibrin glue or other material having adhesive orconnective characteristics may be sprayed on designated portions of thevein (as exemplified at 283 in FIG. 20) and/or the tubular support.Another embodiment includes placement of a material on designatedportions of the lumenal surfaces of the tubular support so as to providethe characteristics of contact adhesion and/or bonding when theseportions contact the vein. However, the glue or other material must notinhibit the function of the tubular support. It is desirable that thecontact of the tubular support with the ablumenal vein segment surfacebe reasonably uniform along the length of the support, and that regionsof much higher force of the support against the ablumenal wall of thevein be avoided.

Applicants have further recognized the need for a device to facilitateassembly of the radially compliant tubular support and a vein segment.It is desirable that such an applicator should not obscure the stentlumen, and that it should allow for easy insertion of the vein. It isfurther recognized that a design whereby diameter is increased by lengthcompression, as in a braided configuration, would allow easy slipping ofthe tubular support over a vein. FIG. 19 illustrates this concept incombination with an applicator 279 to apply the braided support 284 to avein 86. This longitudinal braid contraction phenomena (shown earlier inFIGS. 5 and 6), and which must be carefully managed at the time ofjoining the vein to the stent, is likely quite useful to achieving thegoals of an applicator 279, as noted above. This applicator may alsofacilitate placement of anti-fraying rings 210. In one embodiment, themethod of using the applicator comprises the steps of: providing themeans of longitudinally contracting a stent; holding the stent in thecontracted position with increased stent diameter resulting; inserting avein into the stent lumen; and distending the stent longitudinally whilethe vein is inserted simultaneously until the stent is slipped over thedesired portion of the vein. Further design considerations must ensurethat the stent will not be fixed to the vein in a longitudinallyover-distended or contracted state, so as to ensure that thepredetermined mechanical stent properties remain viable.

FIG. 20 shows an embodiment in which a tubular support 185 is receivedalong the outer surface of surface of an applicator 281 having aninternal passage, and, while passing the vein segment 86 from within theapplicator passage, the tubular support is drawn onto the ablumenalsurface of the vein segment. The applicator here may be a thin walledtube resembling a soda straw.

It is important that the support be applied to a vein at a predeterminedlength which is associated with a particular desired compliance. Alength-defining support feature or system should ensure a predeterminedsupport length. This is particularly true with respect to braidedsupports, and perhaps less important with knit supports in which radialresilience is less dependent upon the amount to which the support isextended axially.

In a braided support, and to a much lesser extend in a knit support,compliance and related mechanical properties are linked to the supportlength through the pitch angle. Imparting a change in length results ina change in pitch angle and compliance. However, the compliance of thesupport is a mandatory characteristic which is optimized, as notedabove, to mimic the compliance of a normal healthy host artery. Whenapplying a support to a vein segment, it is important to accuratelyaccommodate the predetermined tubular support length, even afterlongitudinal contraction of the support for the attachment of thesupport to the vein.

With braided, and to a much lesser extent knit supports, axial supportlength may be controlled, for example, through the use of an axiallyextending, relatively inextensible element, (as for example the thread78 in FIG. 7), that restrains the tubular support from unwanted axialextension. The thread may be woven through the support mesh and may befastened, as by welding, to the various wires that the thread encountersalong the length of the support so that as the support is stretchedaxially, the extent of axial elongation is controlled by the thread asthe thread is drawn taut. Moreover, this feature may enable a length ofthe tubular support to be divided into portions of appropriate length,with the permitted axial extension of each portion controlled by thesection of thread within it. As presently envisioned, a vein segment maybe sheathed in a tubular support as discussed in detail above, with theintent of cutting out a smaller segment of the resulting venous graftfor use in the surgical replacement of an artery, and the venous graftthat is thus used will have vein and tubular support ends that arecoextensive.

Various generally tubular external wire mesh supports were fabricatedfrom metal wires by braiding and by knitting, some being crimped andothers not, and the diametrical compliance of each was measured usingthe in vitro diametrical compliance testing outlined above. The measuredcompliance values were dependent upon many variables, including wiresize, tightness of braid or knit, etc. The following values wereobtained: Compliance Design %/100 mm Hg A Braided Non-crimped 0.9 BBraided Crimped 5.6 C Braided Crimped 1.8 D Knitted Non-crimped 3.4 EKnitted Crimped 7.9 F Knitted Crimped 8.0 G Knitted Non-crimped 10-21 HKnitted Non-crimped  9-21 I Knitted Non-crimped  16->30 J KnittedNon-crimped >30 K Knitted Non-crimped 10-16 L Knitted Non-crimped 21-29M Knitted Non-crimped 22-28 N Knitted Non-crimped >30 O KnittedNon-crimped 10-15 P Knitted Non-crimped  9-11 Q Knitted Non-crimped13-24 R Knitted Non-crimped >30

A surgical procedure is proposed for use of the venous graft disclosedherein. This procedure, which may also be viewed as a simple method forplacement of a venous reinforcement structure, includes, in thisexample, application of the compliant external tubular support duringthe procedure of vein excision. In many instances, vein excision isconsidered a standard part of a surgical operation, which is usuallydone by an assistant at a time when the surgeon is still in thepreparatory phase of the operation.

In one embodiment, an initial step includes dissection and freeing of asaphenous vein. The saphenous vein is dissected free in a standard way,leaving it in situ while ligating and cutting off its branches. Thesecond step involves testing for potential wall leaks of the vein. Inorder to test the isolated saphenous vein for potential leaks, it isnormally cannulated distally and cold heparinised blood is injectedwhile the proximal end is occluded. This inflation of the vein (usingold techniques) with a syringe creates pressures of up to 350 mm of Hgand is often a main reason for traumatic damage of the vein wall.Therefore, a pressure limiting mechanism may be positioned between thevein cannula and the syringe. The external tubular support cannot beapplied yet because leaks in the vein wall need to be freely accessiblefor repair. Therefore, no over-distention protection is placed aroundthe vein yet, necessitating the limitation of the inflation pressure toa level suitable for detecting any leaks of concern but less than alevel deemed to cause unacceptable damage, such as, for example, in oneembodiment, 15 mm of Hg, the pre-maximal dilatation pressure for veins.The tissue remodeling functions of applicants' invention become morecritical in view of the importance of leak testing and the reality ofpossible damage to the intimal layer in the vein during even the mostcarefully performed leak testing.

The next step involves assembling the harvested vein segment and anexternal tubular support of this invention. In this step, the tubularsupport (typified here as a knit support) is mounted on a tube orstraw-like applicator within which is positioned the vein segment. SeeFIG. 20. The straw is then removed axially, leaving the support and veinin contact to form the venous graft. Over-extension of the tubularsupport is prevented using a length-limiting central thread or othermeans, as described above. As required, the vein segment is theninflated under arterial blood pressures of 120 mm of Hg, causing it tocontact the tubular support inner lumenal surfaces. In certainembodiments, an adhesive securing the tubular support to the vein willensure that the vein does not collapse during the surgical procedurewhen no internal pressure is applied. Again, it should be recognized(without limitation) that this is one of several ways to accomplish theabove objectives.

The following sequence may occur at this or another time during theprocedure. One of the external anti-fraying rings or cuffs is slid tothe end of the vein, and a typical double-S-cutting line is used toprepare the end for the first anastomoses. The thin cuff preventsfraying of the tubular support and also gives the vein tissue andtubular support a uniformity which makes the surgical process ofstitching the vein to the host artery in an end-to-side fashion mucheasier. Another thin anti-fraying ring is then slid down from theapplicator to a position where either a side-to-side anastomoses for asequential graft is being performed, or where the vein is being cut atan appropriate graft length. The half of the sliding cuff which remainson the original vein will make the process of the anastomoses to theproximal host artery much easier. In the case of a coronary arterybypass graft, for example, the end of the remaining vein protected bythe other half of the cuff is used for the next distal graftanastomoses.

As structures have become increasingly complex, not only in design butalso in the range of material use, pure analytical methods have begun tofail in describing the behavior of such structures. Due to thescientific challenge of closely matching a vascular graft of the typedescribed herein to a host, analytical methods are rendered somewhatobsolete. Development of a prosthetic vascular graft which mimics themechanical requirements and dynamic compliance of a normal healthyartery is made possible, however, with certain old tools, particularlycut and try methods in which incremental changes are made to thematerial or structure of the tubular support to modify its complianceproperties, and the resulting properties are used to guide furtherchanges. Empirical data or constitutive equations and mathematicalanalyses may be used for certain features. Alternatively, the use ofnumerical modeling with such tools as, for example, Finite ElementModels and Methods, relying on continuum mechanics, along with certainother tools makes this level of customization feasible.

While the embodiments of the invention described herein are presentlypreferred, various modifications and improvements can be made withoutdeparting from the spirit and scope of the invention. The scope of theinvention is indicated by the appended claims, and all changes that fallwithin the meaning and range of equivalents are intended to be embracedtherein.

1. A flexible, resilient, generally tubular external support withinwhich may be supported a vein segment to form a venous graft mimickingthe compliance properties of a healthy artery, the tubular support beingcapable of resilient radial expansion in a manner providing compliancein the range of 3 to 30%/100 mm Hg.
 2. The tubular external support ofclaim 1 in which said support comprises a knit wire mesh.
 3. The tubularexternal support of claim 1 in which said support comprises a braidedwire mesh including an element for controlling the degree of axialextension of the support.
 4. The tubular external support of claim 3 inwhich said element comprises a thread attached to and carried internallyof the support.
 5. The tubular external support of claim 1 including avein segment carried within the support, the vein segment having anablumenal surface in contact with, and supported by, said tubularsupport.
 6. A venous graft for replacement of a section of an artery,the graft comprising a flexible, resilient, generally tubular externalsupport and a vein segment carried within and having an ablumenalsurface in contact with and supported by the tubular support, the venousgraft being capable of resilient radial expansion in a manner mimickingthe compliance properties of an artery.
 7. The venous graft of claim 6wherein said tubular support is capable of said resilient radialexpansion without significant axial dimensional changes.
 8. The venousgraft of claim 6 wherein the compliance of the graft ranges from 3 to30%/100 mm Hg.
 9. The venous graft of claim 6 wherein the externalsupport comprises a generally tubular fiber mesh capable of expanding indiameter through resilient movement of wires of the mesh to accommodateradial expansion of the vein segment supported in it sufficient toprovide the graft with said compliance.
 10. The venous graft of claim 6wherein said external support comprises a knit, tubular mesh capable ofexpanding radially to accommodate radial expansion of the vein segmentsupported in it within said compliance range.
 11. The venous graft ofclaim 6 wherein said external support comprises a braided fiber mesh soconfigured as to exhibit radial expansion in said compliance rangewithout significant reduction in the axial length of the support. 12.The venous graft of claim 11 wherein said fiber mesh is made of metalwire.
 13. The venous graft of claim 12 wherein said metal wire is ofstainless steel or of a cobalt chrome alloy.
 14. The venous graft ofclaim 11 wherein said metal wire is a shape memory alloy.
 15. The venousgraft of claim 11 wherein said fiber mesh is polymeric.
 16. The venousgraft of claim 6 wherein the ablumenal surface of the vein segment isbonded to said tubular support.
 17. The venous graft of claim 6 whereinthe vein segment and the tubular support are axially coextensive. 18.The venous graft of claim 10 wherein said knitted tubular fiber mesh ismade from crimped fibers.
 19. The venous graft of claim 9 wherein saidtubular fiber mesh is made from fibers that are crimped after havingbeen formed into said tubular mesh.
 20. A venous graft for replacementof a section of an artery, the graft comprising a flexible, resilient,knit wire mesh configured as a generally tubular external support and avein segment carried within and having an ablumenal surface in contactwith and supported by the tubular support, the support having resilientradial expansion and contraction characteristics that provide the venousgraft with compliance properties mimicking those of an artery.
 21. Thevenous graft of claim 1 wherein the compliance of the venous graftranges from 3 to 30%/100 mm Hg.
 22. Method of producing a venous graftfor use in replacing a section of an artery, comprising providing asegment of a vein and sheathing the segment in a generally tubularsupport in supportive contact with the ablumenal surface of the veinsegment, the support being sufficiently flexible and radially resilientas to provide the graft with compliance properties mimicking thecompliance properties of an artery.
 23. The method of claim 22 includingthe step of cutting said venous graft from a longer section of veinsheathed in said tubular support, the ends of the vein and tubularsupport of the venous graft being coextensive.
 24. The method of claim22 including the step of supporting said generally tubular support uponan exterior surface of an applicator having an internal passage withinwhich is positioned the vein segment, and removing the applicator topermit the tubular support to come into supportive contact with theablumenal surface of the vein segment.
 25. The method of claim 22including the step of supporting said generally tubular support upon anexterior surface of an applicator having an internal passage, and, whilepassing the vein segment from within the applicator passage, drawing thetubular support onto the surface of the vein segment.
 26. The method ofclaim 22 wherein said generally tubular support is chosen to besufficiently radially resilient as to provide the venous graft with acompliance ranging from 3 to 30%/100 mm Hg.
 27. The method of claim 24wherein said tubular support is axially resilient, the method includingthe step of controlling axial dimension changes of the tubular supportas the support comes into supportive contact with the vein segment toprovide the venous graft with said compliance properties.
 28. The methodof claim 27 including the step of providing the tubular support with anaxially extending, relatively inextensible element that restrains thetubular support from unwanted axial extension.
 29. The method of claim28 wherein said inextensible element comprises a flexible fiberpositioned within the tubular support and between the tubular supportand the ablumenal surface of the vein segment.
 30. The method of claim28 wherein the flexible fiber is a wire joined to the interior of thetubular support.
 31. The method of claim 22 including the step ofbonding the ablumenal surface of the vein segment to the tubularsupport.
 32. The tubular external support of claim 1 in which said aknit wire mesh support comprises loops that alternate in sizecircumferentially of the support.
 33. The method of claim 22 includingforming said tubular support from a knit wire mesh, wherein said mesh isformed with loops that alternate in size circumferentially of thesupport.